The vision of the program is to create physiologically based mathematical models to interpret data from contemporary PET/CT and to implement these models in the clinical management of liver patients using established and novel PET-tracers. Today, examinations of the livers multiple functions are either non- specific or difficult to perform. The overall aim of our program is to develop and implement dynamic PET/CT methods that can significantly improve our understanding of the disturbed liver metabolism in the large groups of patients suffering from liver disease. Specific aims are 1) non-invasive determination of hepatic dual input function, 2) liver microcirculation, 3) hepatic arterial buffer response, 4) tracer kinetics of regional metabolism and biliary excretion, and 5) specific molecular transport defects in liver diseases detected by dynamic, high resolution PET/CT. Design and Methods: A bench-to-bedside design constitutes the study. Based on knowledge of liver physiology, pathophysiology, and biochemistry we create new mathematical models applicable to dynamic PET/CT. We test, validate, challenge, and refine these models in pig studies before translation into human studies. Models for determining tracer input from the portal vein and the hepatic artery (dual input function) and microcirculation of the liver are investigated with 11 CO-PET and contrast-CT in anaesthetized pigs, validated with independent invasive procedures, and challenged by controlled interventions of the flow and metabolism. The refined, statistically sensitive and specific models are then translated as non-invasive procedures into humans (healthy controls and patients). 11C-Methionine and 18FDGal are investigated as suitable radio-labeled PET tracers for measuring the total and regional hepatic metabolism. To measure biliary excretory function, novel tracers (11C-RAL-01,11 C-verapamil, 11C-ICG and 18F-taurocholate) are developed and tested thoroughly in pig studies before tested in humans. Liver biopsies (pigs) and blood samples (pigs and humans) are analyzed by radio-HPLC to determine the time course of radio-labeled metabolites and to optimize kinetic modeling of tracer metabolism. The microscopic distribution of tracers in benign and malignant liver tissue is evaluated by single- and dual-tracer autoradiography. We will create new, non-invasive methods for measuring blood flow and function in the liver using sensitive PET/CT scanning. This will lead to improved diagnosis and treatment of the large groups of patients with liver disease and cancer in the liver.